New insights into the contribution of EBV to MS pathogenesis

New research showed that patients with genetic risk factors who were infected with one of the strains of Epstein-Barr virus (EBV) that upregulates immunomodulatory human leukocyte antigen E (HLA-E), had up to 260-fold increased risk of developing MS. The authors claim that these results allow the early identification of patients at risk for MS and suggest new therapeutic options against MS.

EBV is a ubiquitous herpes virus that persistently infects >90% of adults. Infection with EBV has been identified as one of the strongest risk factors for MS. Prof. Thomas Berger (Medical University of Vienna, Austria) explained that this elevated risk of MS is linked to the development of high-level Epstein-Barr nuclear antigen (EBNA)1-specific antibody titres in some people. This is probably because EBNA1-derived antigen (EBNA_386–405) has a very similar molecular structure to the CNS-derived glial cell adhesion molecule (GlialCAM_370–389). However, EBNA_386–405-specific immune responses also occur in healthy individuals. Therefore, Prof. Berger and colleagues aimed to identify factors that determine when people with high-levels of EBNA_386–405-specific autoimmune responses against the GlialCAM_370–389 develop MS. To this end, they studied data from 270 EBV-positive MS patients who had blood samples available dating back to when they were infected with EBV, which occurred a median of 8.2 years before MS diagnosis. A matching set of 270 samples from healthy individuals were also analysed. Of these, 108 had high levels of EBNA1 antibodies (EBNA^high), while 162 had low levels (EBNA^low).

The researchers found that initial immune responses targeting EBNA1 and GlialCAM were very similar in participants who did or did not develop MS. However, the following differences between MS patients and healthy controls with EBNA^high were found:

• Natural killer group (NKG) 2C+ and NKG2D+ cells, 2 types of potent NK cells, were increased in EBNA^high healthy controls, but not in MS patients.
• Cellular resistance to cytotoxicity via NK cells depends on expression of the immunomodulatory HLA-E. EBV-reactivation in infected B cells triggers HLA-E expression, and the EBV-encoded latent membrane protein-1 (LMP-1) thereby induces IL-27 secretion.
• Different EBV-variants encode for different variants of LMP-1 peptides with affinity for HLA-E. Prof. Berger noted that “MS patients differ from EBNA^high healthy controls in that they use 2 of these peptides, which are crucial for complete inhibition of NK cell responses.”
• The defined virus and host genetic pre-dispositions are associated with an up to 260-fold increased risk of MS.
• EBV-specific, HLA-E-restricted CD8+ T cells eliminate EBV-infected GlialCAM-specific B cells in EBNA^high healthy controls, but not in MS patients. This response is partly driven by the host's genetic HLA-E variants encoding HLA-E*0101 and HLA-E*0103 alleles.

Prof. Berger concluded that there are virus- as well as host-specific genetic pre-dispositions which cause ineffective control of EBV-mediated autoimmune responses.

1. Berger T, et al. Ineffective immune control of Epstein-Barr virus-induced autoreactive responses is an important cause of multiple sclerosis. O183, MSMilan 2023, 11–13 October, Milan, Italy.

 

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Posted on 4 December, 20234 December, 2023